A tissue-specific gene and drug delivery system has long been considered important for drug discovery and pharmaceutical advancement because most drugs are systemically delivered and circulated in the body when administered to a patient, which might adversely affect healthy organs or cells. The tissue-specific delivery system allows the accumulation of a high drug concentration at the target tissue which eliminating adverse side effects, leading to efficient treatment of tissue-specific diseases.
Some liver diseases arise from infection by pathogenic viruses, e.g., HBV (hepatitis B virus) and HCV (hepatitis C virus), while non-infectious liver diseases result from exposure to liver-toxic materials, or genetic or environmental disorders. The progression of early-stage liver diseases caused by biological stimuli ultimately leads to chronic hepatitis, liver cirrhosis or hepatocellular carcinoma (HCC). Among several drug or gene delivery systems currently studied in the treatment of such liver diseases, a lipoprotein system, mainly that of HDL. (high density lipoprotein), has advantages over other delivery systems which use viral vectors (Wang X., et al., Gene Ther (2006), 13: 1097-1103), non-viral complexes (Landen C. N., et al., Cancer Res. (2005), 65: 6910-6918; Morrissey D. V., et al., Nat. Biotechnol. (2005), 23: 1002-1007; Sorensen D. R., et al., J. Mol. Biol. (2003), 327: 761-766; and Urban-Klein B., et al., Gene Ther (2005), 12: 461-466) and antibodies (Song E., et al., Nat. Biotechnol. (2005), 23: 709-717). For example, the lipoprotein can be preferably recognized and taken up via cell surface receptors specific for liver cells (Firestone R. A., Bioconjug. Chem. (1994), 5: 105-113; de Smidt P. C., et al., Crit. Rev. Ther. Drug Carrier Syst. (1990), 7: 99-120; and Filipowska D., et al., Cancer Chemother Pharmacol. (1992), 29: 396-400), and it is an endogenous product which is not detrimental to human and does not trigger immunological responses in clinical applications (Pussinen P. J., et al., Biochem. Biophys. Acta. (2000), 1485: 129-144).
Recently, there has been a report that a recombinant high density lipoprotein (HDL) can be used as a carrier for delivering a lipophilic antitumor drug into human hepatocellular carcinoma cells by taking advantage of the hydrophobic cholesterol ester-loading properties of HDL (Lou B., et al., World J. Gastroenterol. (2005), 11: 954-959). However, it has merely been demonstrated in vitro, but not in vivo, that the cellular uptake of the HDL carrier by a hepatoma cell line, SMMC-7721, is higher in compared with a normal liver cell line, L02, and the limitation in tissue-specific targeting remains to be solved.
The present inventors have therefore endeavored to develop an effective system for liver-specific delivery of a therapeutic drug, and have found that a composite comprising an apolipoprotein A-I and a liposome-forming material can specifically deliver and release therapeutic drugs to the liver.